Due to the widespread emergence of drug-resistance, diseases caused by bacterial pathogens have become a major public health concern in recent years. There is an urgent need for the development of new antimicrobials, especially those that have a new target, in order to overcome drug resistance. Bacteria generally develop drug resistance in three ways: production of metabolizing enzymes for the degradation of the drugs, modification of their targets to render the drugs ineffective, and expression of high levels of efflux proteins that “pump” the drug out of cells resulting in the lowering of drug concentration inside. Therefore, the most promising approaches to finding new antimicrobials include (1) searching for new targets, (2) inhibiting or overcoming efflux, and (3) inhibiting metabolic enzymes.
SecA, an indispensable ATPase of the protein translocation machinery is present in all bacteria. SecA is responsible for the secretion of many vital proteins, important toxins and other virulence factors, and is essential for bacterial survival. SecA has no counterpart in mammalian cells, thus providing an ideal target for developing antimicrobial agents. SecA functions as a membrane protein, forming a transmembrane channel and thus provides the possibility for antimicrobial agents to reach this target without entering into the cells. In such a case, the drug efflux pump would have less negative effects on the inhibitor's ability to exert antimicrobial activity. In addition, because SecA is present in all bacteria, this is a target for the development of broad-spectrum antimicrobials.
Inhibitors of SecA can be potential antimicrobial agents. However, inhibitor development for SecA had not been an active area of research until recently, presumably due to the difficulty in working with this membrane protein and the active translocation complex. To date, inorganic azide was the only known SecA inhibitor with an IC50 at the mM range. However, azide is also an inhibitor of many other enzymes such as cytochrome c oxidase, superoxide dismutase, alcohol dehydrogenase, and ceruloplasmin. Additional SecA inhibitors with potencies in the high μM to low mM range have been reported.
There exists a need for new SecA inhibitors which have activity in the low or high nanomolar to low micromolar range.
Therefore, it is an object of the invention to provide SecA inhibitors which have activity in the low or high nanomolar to low micromolar range and methods of making and using thereof.